Central Sleep Apnea in Chronic Congestive Heart Failure: Update and Implications for Management

Jack J. Salah, M.D., FCCP, DABSM

 
Over the past decade, the diagnosis and management of obstructive sleep apnea has received considerable attention in sleep medicine. Its impact on daytime cognitive function and cardiovascular health is increasingly recognized, and its frequency in the adult population (2-4%) renders it the most common pathologic diagnosis in sleep laboratories. However, among cardiac patients with left ventricular dysfunction, Cheyne-Stokes respiration with Central Sleep Apnea (CSR-CSA) is more prevalent, and mounting evidence suggests that this diagnosis may have important implications for outcome and management of CHF. Although Central sleep apnea (CSA) may be idiopathic (rare), or secondary to CNS pathology (typically CVA), the most frequent association is chronic CHF. This paper will deal primarily with that entity.

Central sleep apnea is defined as repetitive episodes of airflow cessation > ten seconds as a result of absent respiratory effort (Figure 1). As there is no ventilatory motor output, snoring* or other signs of upper airway resistance are characteristically absent. (*Snoring may coexist with central apneas in certain patients with obesity or other risk factors.) These episodes occur predominantly in non-REM sleep and are usually associated with arousals or desaturation; they typically disrupt sleep, and may trigger other adverse events, such as nocturnal angina or dysrhythmias. 2,3

 
The pathophysiology of CSR-CSA invokes two key mechanisms (Table 1). One is a tendency for baseline hyperventilation. In CHF, this appears largely due to pulmonary venous congestion with chronic stimulation of vagal afferent lung receptors. Studies of cardiac patients with CSR-CSA have indicated lower wake and sleep pCO2 levels than in patients without CSR-CSA. 4

As breathing control in non REM sleep is largely under the influence of chemical stimuli (esp. pCO2), hyperventilation creates a low pCO2 state that may trigger apnea as one transitions from wakefulness to non REM sleep. A second component is the delay in circulation time seen in low cardiac output states (i.e. delay in blood pCO2 signal to chemoreceptors). This may be associated with a destabilization of the feedback control of breathing with a delayed overshoot in the ventilatory response to stimuli. That is, prolonged periods of central apnea or hypopnea (underbreathing in response to hypocapnic hyperventilation) alternate with exaggerated periods of ventilation (overbreathing and arousals in response to apnea) perpetuating a repetitive vicious cycle.

In various studies of cardiac patients with ejection fraction <45%, the prevalence of sleep apnea in patients undergoing polysomnography was 40-68%. 3,5,6 The majority of these had CSR-CSA, with a smaller subset having obstructive sleep apnea. These cardiac patients demonstrated higher levels of sleep disruption, desaturation, and nocturnal dysrthymias than did nonapneic patients with similar levels of LV dysfunction. Excessive daytime sleepiness, as assessed by the Epworth Sleepiness Scale and by lower scores on Multiple Sleep Latency Testing, is a common problem.7 Survival also appears to be adversely affected in CHF patients with CSR-CSA. Hanley et al 8 reported a 3 year mortality of 56% in CHF patients with CSR-CSA, compared to 11% in patients without CSR-CSA despite comparable LV function. More recently, Lanfranchi et al 9 prospectively studied outcome in 62 CHF patients with LV EF <35%. They demonstrated that the Apnea Hypopnea Index (AHI) was the most powerful independent predictor of survival, with a two year mortality of 50% in patients with an AHI >30, vs. 26.2% in patients with an AHI <30. Therefore CSR-CSA appears to portend a poorer prognosis in patients with CHF.

Treatment of CSR-CSA

Improvement in CHF through ACE inhibitors and beta blockers has been associated with a reduction in mortality, and may improve CSR-CSA events in some patients; however, many patients will continue to have apneic episodes. In the largest and longest ACE inhibitor study to date, enalapril reduced the death rate compared with placebo, but after 3 1/2 years, mortality still approached 35%. Additional novel treatment strategies that impact on the pathophysiology of CHF are highly needed.

Prevention of hypoxemia induced hyperventilation with nocturnal oxygen therapy has reduced episodes of CSR-CSA in some, but not all patients. 10,11, 12 Andreas et al 13 also demonstrated a modest improvement in sleep architecture and exercise capacity in CSR-CSA patients treated with nocturnal oxygen. Likewise, data supporting the use of theophylline in CSR-CSA appear in the literature (though largely anecdotal). In one controlled study 15, a five day course of theophylline therapy acutely reduced, but did not eradicate, CSR-CSA; no improvement in sleep architecture was seen and the affect on daytime sleepiness/fatigue was not assessed. Therefore, following maximal medical therapy in CHF, oxygen or theophylline may be tried in selected patients (i.e those with nocturnal hypoxemia may benefit from an oxygen trial, while those with coexistent COPD may benefit from judicious theophylline). The role of these agents in the overall outcome of disease, however, remains to be ellucidated.
CPAP is the most effective therapy currently available for the treatment of CSR-CSA, and it has intriguing possibilities for the ancillary management of underlying CHF. Though CSR-CSA is a consequence, and not a primary cause of CHF, mounting evidence suggests that it adversely influences outcome in CHF, and that it is modifiable factor. Through various mechanisms, CPAP has been shown to improve cardiac function, respiratory function, and sleep quality in patients with CSR-CSA with CHF (Table 2, 3).

Nocturnal CPAP raises the sleep pCO2 slightly, thereby ameliorating the tendency for hypocapnia induced apnea. CPAP also increases F R C and improves inspiratory muscle function. 16 Related benefits include a reduction in daytime fatigue and sleepiness and an improvement in NYHA functional class. 17


 

 

CPAP has been shown to improve LV function in congestive heart failure. 5,18,19,20 The acute benefit is related to mechanical preload and afterload reduction; the more sustained benefit over time is likely related to a downregulation of sympathetic tone. Increased sympathetic nerve activity as reflected by elevated plasma norepinephrine 21 and cardiac norepinephrine spillover 22 is a risk factor for mortality in CHF. Van de Borne et al 23 recently showed that in patients with severe CHF, muscle sympathetic nerve activity was higher during periods of CSR compared to periods without CSR. In a related study, Waravdekar et al showed that patients with obstructive sleep apnea also have high sympathetic nerve activity, and that this activity is ameliorated with CPAP therapy. 24

Naughton et al recently studied 35 optimally treated CHF subjects with and without CSR-CSA. 25 They demonstrated that the CSR-CSA group had higher urinary norepinephrine and morning plasma norepinephrine than the cardiac group without CSR-CSA. The concentration of norepinephrine was directory related to the degree of apnea, arousals, and nadir desaturation but not to the degree of LV dysfunction. Moreover, when restudied after one month of nocturnal CPAP therapy, the CPAP group had a significant reduction in both plasma and urine norepinephrine levels compared to medically treated controls. Takova et al 26 have shown that mitral regurgitant fraction and elevated ANP levels (both associated with a poor prognosis in CHF) are also ameliorated after three months of CPAP therapy in patients with severe CHF and CSR-CSA. Collectively these data suggest that though CSR-CSA does not cause CHF, it propagates the pathophysiology of CHF by further elevating sympathorenal through apneas, arousals, and hypoxemia. These adverse events appear largely reversible by CPAP administration.

Until recently, there has been no prospective data on the effect of CPAP therapy on the long term outcome of CHF with CSR-CSA. Sin et al have now studied 66 patients with severe CHF (29 with and 37 without CSR-CSA) who were randomized to CPAP therapy or optimal medical therapy. 20 They were followed for a median of 2.2 years, and treatment analysis revealed that patients who used CPAP experienced a significant reduction in mortality and time to transplantation than the control group (25% event rate in CPAP users vs. 56% in the control group, indicating a relative risk reduction of 81%). Currently a multicenter trial (Canadian Positive Airway Pressure Trial for Heart Failure or "CANPAP") is underway in hopes of validating these promising data.

In summary, congestive heart failure is exceedingly common in our society, occurring in approximately 1% of adults, or over 4 million Americans today. CSR-CSA, though also prevalent in these patients, is often overlooked by cardiologists and primary care physicians, and its implications for outcome and management are likely underappreciated. Consider Central sleep apnea in any CHF patient with an ejection fraction of <45% and excessive sleepiness or witnessed apneas or CSR during sleep. Where appropriate, diagnostic polysomnograghy and a thoughtful treatment plan may improve outlook in an otherwise devastating disease.

References

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Jacksonville Medicine / March, 2001

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